Noroviruses are a significant cause of epidemic and sporadic gastroenteritis worldwide. They are the leading cause of severe childhood diarrhea in the United States and a major cause of severe childhood diarrhea in developing nations. Thus, development of effective vaccines and therapeutics is a critical need. The major barrier to this development has been the inability to culture human noroviruses. We have made two remarkable discoveries to overcome this obstacle - (1) human noroviruses infect B cells; and (2) they require enteric bacteria for optimal infection. Using the well-developed murine model of norovirus infection, we have validated both of these features of infection in an in vivo setting. Moreover, both of these findings provide fundamentally important clues to understanding norovirus pathogenesis and to developing effective strategies to combat infection. We speculate that human noroviruses interact with commensal bacteria in the gut lumen and virus:bacteria complexes are transcytosed across the intestinal epithelium in order to access the underlying B cell targets. During this process, the commensal bacteria should be recognized by mucosal immune cells and stimulate a tolerogenic microenvironment. In this environment, development of immune responses to the virus should be curbed through a process termed bystander suppression. This model is supported by the long- standing knowledge that norovirus infections are noninflammatory and they fail to elicit robust protective immunity. Understanding the basis for this apparent weak immunogenicity is key to designing effective treatment approaches. The objectives of the proposed research are thus to elucidate the mechanism by which enteric bacteria facilitate norovirus infection of B cells (Specific Aim 1); and the immune consequences of this interaction (Specific Aim 2).